CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 782

messenger RNA levels, respectively. 540 - 542 Moreover, phosphorylation has been hy-
pothesized to affect OAT activity posttranslationally: The epidermal growth factor
(EGF) has been reported to induce OAT activity, whereas protein kinase C and certain
protein kinase C activators (e.g., phorbol esters) led to an inhibition/internalization
of human OAT1. 543 , 544

Pharmacological and Toxicological Function Given the increasing number of drugs
discovered to be OAT substrates, study of the pharmacological and toxicological roles
of OATs has acquired clinical relevance. The recent generation of OAT gene knockout
mice has provided in vivo models for this purpose, although the presence of species
differences in substrate specificity and tissue distribution between OATs always has
to be considered. Moreover, due to the functional redundancy of OATs, generation of
knockout of multiple OAT genes (e.g., OAT1 − / − /OAT3 − / − or OAT4 − / − /URAT1 − / − )
is expected to help further in the elucidation of the in vivo function of these clinically
relevant transporters. Both Oat1 and Oat3 knockout mice recently developed appeared
healthy and viable and did not exhibit any obvious phenotype. Oat1 knockout mice
showed a significant loss of renal organic anion secretion and markedly increased
plasma levels of a wide range of endogenous (e.g., benzoate, N -acetylaspartate, 4-
hydroxyphenyllactate, 4-hydroxyphenylpyruvate, 4-hydroxyphenylacetate) and spe-
cific exogenous compounds, some of which have been demonstrated to interact with
OAT1 in vitro. For instance, in Oat1 knockout mice a reduced renal excretion of the
loop diuretic furosemide (a well-known OAT1 substrate) was demonstrated, result-
ing in altered diuretic effect of this drug. Similarly, OAT1 can be predicted to affect
the pharmacokinetics of other clinically used substrate drugs (

-lactam antibiotics,
NSAIDs, antiviral nucleoside analogs), and the concomitant treatment with OAT sub-
strates and inhibitors may lead to a reduction in renal clearance and to an increase in
plasma levels and the half-lives of substrate compounds, thus potentially increasing
the risk of their extrarenal toxicity. 545 For instance, drug-drug interactions between
the antifolate methotrexate (a well-known OATs substrate) and penicillin, probenecid,
and NSAIDs, have been reported to determine life-threatening complications due to
severe myelosuppression caused by a decreased methotrexate renal secretion. 528
Oat3 knockout mice have recently been generated. They display an altered organic
anion transport physiological phenotype in renal and choroid plexus epithelia. In
ex vivo experiments, uptake of Oat1 substrates, in particular taurocholate, but also
estrone sulfate and to a lesser extent PAH, was reduced significantly in renal slices pre-
pared from Oat3 knockout mice compared with slices from wild-type mice. Similarly,
using intact choroid plexus, uptake of the Oat substrate fluorescein was markedly re-
duced in Oat3 knockout mice compared with wild-type mice. These findings suggest
that at least in mice, Oat3, together with other members of the OAT family and other
organic anion transporters, may play an important role in drug distribution and in
brain protection from toxic injury by regulating the composition of the extracellular
fluid of the central nervous system. 546
Moreover, renal toxicity of several clinically used drugs (tetracyclines, cephalori-
dine, adefovir, cidofovir) as well as nephrotoxins (ochratoxin A, citrinin, mercuric